Formulation adverse events caused

Increasing the concentration increases the penetration, but not to the same degree. Solubility of the corticosteroid in the vehicle is an other determinant of absorption and efficacy. So different formulations of the same corticosteroid can end up in a different efficacy classification. Efficacy can be further augmented by using the corticosteroid under occlusion. Occlusion with plastic enhances penetration and also absorption. However, with increased absorption also the risk of systemic side-effects increases. Systemic absorption will suppress the pituitary-adrenal axis and may cause Cushing s syndrome and a plethora of other adverse events (see Chapter 24, Section Il.b). Even small amounts absorbed may already cause growth retardation in children. 

Once-daily administration of modified-release formulation of fluvastatin 80-320 mg/day was generally safe and well tolerated in 40 patients with primary hypercholesterolemia over 13 days (7). However, fluvastatin 640 mg in this formulation was not well tolerated six of seven patients had adverse events, including diarrhea, headache, and rises in serum transaminases. In addition, the pharmacokinetics of fluvastatin were non-linear at this dose, possibly because of saturation of first-pass metabolism, causing higher than expected serum drug concentrations. 

Doxazosin can cause a sharp fall in blood pressure at the start of therapy, and a modified-release formulation has been developed in an attempt to obviate this. In an open, non-comparative, sequential study in primary care, the ordinary formulation (1-16 mg/day for 3-6 months) was replaced by the modified-release formulation (4—8 mg/day for 3 months) in 3537 patients (8). The most common reasons for withdrawal from the study were loss to follow-up (37%) and adverse events (28%). Blood pressure fell from 160/95 to 139/82 mmHg with the ordinary formulation and to 135/79 mmHg when the modified-release formulation was used instead. The most common adverse events were weakness, headache, dizziness, and hypotension, all of which were more common with the ordinary formulation. However, these differences could have been due to a healthy survivor effect, in which those who had an adverse event early on (that is while taking the ordinary formulation) dropped out before taking the modified-release formulation, which would therefore appear to be safer. Thus, the lack of crossover in this study makes the results hard to interpret, although it appears that the two formulations were at worst no different from each other. 

When developing formulations for compounds with limited solubility or stability, where extremes of pH or co-solvents might be used, it is desirable to carry out screening studies to assess their potential to cause pain or other adverse events following injection. Haemolysis and phlebitis may occur as a consequence of IV therapy, whilst pain may occur on administration of any type of injection. Several in vitro and in vivo models have been developed to evaluate the potential for adverse effects following parenteral administration these are discussed briefly below. For a more detailed discussion of this subject, the reader is referred to the excellent review by Yalkowsky et al. (1998). 

The major euthanasia agents used in veterinary medicines are the barbiturates and these have already been discussed in Chapter 5. When formulated for euthanasia, these products, and indeed other products used for this purpose, are not normally sterile unlike other parentally, and especially intravenously, administered formulations as this is considered unnecessary as the patients concerned will not recover from the effects of the drug and so the secondary effects of bacteria and other extraneous agents are irrelevant. The products are often frequently formulated with a dye to distinguish them from other similar but sterile formulations. Euthanasia agents differ from all other veterinary medicinal products in pharmacovigilance terms in that lack of efficacy, that is failure to cause death of the patient, is a reportable adverse event (lack of expected efficacy). 

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